Exploration of suitable pharmacodynamic parameters for acarbose bioequivalence evaluation: a series of clinical trials with branded acarbose.

AIMS: To determine deficiencies in the FDA's guidance for assessing acarbose bioequivalence (BE) and to explore optimal pharmacodynamic (PD) metrics for better evaluation of acarbose BE. METHODS: Three clinical trials with branded acarbose were conducted in healthy subjects, including a pilot study (Study I, n=11, 50 and 100 mg), a 2X2 crossover BE study (Study II, n=36, 100 mg) and a 4x4 Williams study (Study III, n=16, 50/100/150 mg). Serum glucose concentrations were measured by the glucose oxidase method. RESULTS: In Study I, compared with 50 mg acarbose, only 100 mg acarbose had a significantly lower Cmax0-4h than that of sucrose administration alone (7.96+/-0.83 mmol/L vs 6.78+/-1.02 mmol/L, P<0.05). In Study II, the geometric mean ratios (GMRs) of the test formulation to the reference formulation (both formulations were the branded drug) for FDA PD metrics, DeltaCmax0-4h and DeltaAUC0-4h , were 0.903 and 0.776, respectively, and the 90% confidence intervals (CI) were 67.44-120.90 and 53.65-112.13, respectively. The GMRs (CI) for possible optimal evaluation PD metrics (Cmax0-2h and AUC0-2h ) were 1.035 (94.23~112.68) and 0.982 (89.28~107.17), respectively. Further, Cmax0-2h and AUC0-2h also met the sensitivity requirements for BE evaluation in Study III. CONCLUSIONS: Considering the mechanisms of action of acarbose, the PD effect was shown to be dose-independent during the 2-4 h period post-administration of acarbose. Hence PD metrics based on the serum glucose concentration from 0 to 2 h (Cmax0-2h and AUC0-2h ) are more sensitive than the FDA-recommended PD metrics for acarbose BE evaluation from 0-4 h (DeltaCmax0-4h and big up tri, openAUC0-4h ).